Systems, compositions, and methods for local imaging and treatment of pain

ABSTRACT

Pain factors are labeled with targeted agents or markers delivered into the body. The labeled pain factors are imaged with appropriate imaging tools in a manner allowing selective identification and localization of areas of pain source or transmission. The labeled pain factors allow spatial differentiation in the imaging sufficient to specify the location of the pain so as to drive therapeutic decisions and techniques in order to treat the pain. Pain factors labeled and imaged in this manner may include one or more of nerve factors, blood vessel factors, cellular factors, and inflammation factors. Labeled markers may include for example radioactive materials (e.g. tritiated or iodinated molecules) or other materials such as metal (e.g. gold) nanoparticles. Intermediary binding materials may be used, such as for example bi-specific antibodies. Therapeutic components of the system and method include for example localized energy delivery or ablation treatments, or local drug or other chemical delivery. Locations containing pain factor selectively bound by targeted agents are selectively treated with directed energy into a region containing the targeted agent bound to the pain factor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/158,610 filed on Oct. 12, 2018, which is a continuation of U.S.patent application Ser. No. 14/850,945 filed on Sep. 10, 2015,incorporated herein by reference in its entirety, which is acontinuation of U.S. patent application Ser. No. 12/053,379 filed onMar. 21, 2008, now U.S. Pat. No. 9,161,735, incorporated herein byreference in its entirety, which is a 35 U.S.C. § 111(a) continuation ofPCT international application number PCT/US2006/036943 filed on Sep. 21,2006, incorporated herein by reference in its entirety, which claimspriority to, and the benefit of, U.S. provisional patent applicationSer. No. 60/719,670 filed on Sep. 21, 2005, incorporated herein byreference in its entirety, and which claims priority to, and the benefitof, U.S. provisional patent application Ser. No. 60/750,990 filed onDec. 15, 2005, incorporated herein by reference in its entirety.Priority is claimed to each of the foregoing applications.

The above-referenced PCT international application was published as PCTInternational Publication No. WO 2007/035906 on Mar. 29, 2007, whichpublication is incorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with Government support under AG017762, awardedby the National Institutes of Health (NIH). The Government has certainrights in the invention

NOTICE OF MATERIAL SUBJECT TO COPYRIGHT PROTECTION

A portion of the material in this patent document is subject tocopyright protection under the copyright laws of the United States andof other countries. The owner of the copyright rights has no objectionto the facsimile reproduction by anyone of the patent document or thepatent disclosure, as it appears in the United States Patent andTrademark Office publicly available file or records, but otherwisereserves all copyright rights whatsoever. The copyright owner does nothereby waive any of its rights to have this patent document maintainedin secrecy, including without limitation its rights pursuant to 37C.F.R. § 1.14.

BACKGROUND OF THE INVENTION 1. Field of the Invention

This invention pertains generally to imaging of tissues associated withskeletal joints. More particularly, it relates to identification and/orcharacterization of localized factors associated with musculoskeletalpain using labeled markers and related imaging tools.

2. Description of Related Art

Chronic back pain (i.e. generally persisting longer than 12 weeks) isamong the most prevalent and expensive non-lethal conditions in theUnited States, and is believed to be the most common cause of disabilityin persons under 45 years old. The number of people suffering fromchronic back pain is estimated to exceed 25% of the overall population.Every year, about 3-4% of the U.S. population is estimated to bedisabled temporarily, and about 1% of the working age population isestimated to be disabled totally and permanently, due to intractableback pain. An estimated 11.7 Million patients present medically withchronic back pain. National disability expenses for this prevalentcondition range from $30-$70 billion per year. Effectively treating thisprevalent condition remains among the largest unmet clinical needs inmedicine. Properly diagnosing and localizing the source of pain alsoremains a significant shortcoming on the critical path toward providingsuch therapy in a targeted manner with predictably successful outcomes.

Diagnosis of the location, mode, and extent of disc degeneration isoften used as a precursor tool to drive therapy for treating back pain.However, such measures are often not specific enough to localize theexact site in or around a degenerating disc where pain is beingexperienced. Also, a direct correspondence is not always found betweendisc degeneration and back pain. Consequently, existing imagingmodalities that identify (and even quantify) disc anatomy, such as CT orMRI, are not always helpful at localizing sources of back pain in manycases.

Accordingly, there is still a substantial need for new imagingmodalities to objectively, accurately, and specifically identify andlocalize source(s) of pain, and in particular back pain, and still moreparticularly lower lumbar back pain. There is in particular such a needwith respect to identifying painful discs in an improved way, and tolocalize within or around those discs the specific site of injury orsource of pain in an improved, predictable, dependable manner.

BRIEF SUMMARY OF THE INVENTION

Accordingly, certain aspects of the present invention provide a system,composition of matter, and method that better describe, diagnose, andlocalize of the sources of pain in and around musculoskeletal joints,and in particular beneficial modes in and around spinal discs inrelation to back pain.

Among the various modes employed according to this aspect, oneparticular beneficial mode involves artificially labeling substanceslocally in the area of back pain, such as in a particular beneficialexample the spinal motion segment, that are known suspects to paingeneration and transmission, such as for example disc, facet joints, andvertebral bodies.

Two particularly beneficial embodiments according to this mode, usefuleither alone or in combination, include: (a) labeling nerves, and inparticular beneficial embodiments nociceptors, and (b) labeling chemicalfactors that irritate nerves, (c) labeling cells that produce chemicalfactors that irritate nerves; and (d) labeling blood vessels that aretypically in close approximation to nerves.

In addition to the significant benefit provided by these approaches forclinical diagnosis, they are also considered highly beneficial inproviding new avenues to drive choices for therapeutic approaches.

One aspect of the invention is a method for conducting a medicalprocedure related to a localized, active source of pain at a locationwithin a patient. This method includes artificially labeling a painfactor at the location in a manner substantially increasing the abilityto image the pain factor with an imaging tool. The labeled pain factoris then labeled in a manner sufficient to selectively differentiate afirst concentration of the labeled pain factor at the location versus asecond concentration of the labeled pain factor in tissue adjacent tothe location.

According to one highly beneficial mode, the location is associated witha skeletal joint.

Another mode of this aspect further includes delivering a substantiallytargeted label into the patient that is adapted to differentially bindto and label a pain factor associated with the source of pain at thelocation. The pain factor at the location is artificially labeled bybinding the pain factor with the targeted label.

According to one embodiment, the differential binding comprises specificbinding to the pain factor.

According to another embodiment, the differential binding comprisesnon-specific binding to the pain factor.

According to another mode, the pain factor comprises at least one of anerve factor, an inflammatory factor, a cellular factor, or a bloodvessel factor, or a combination thereof.

In one more particular mode, the pain factor comprises a nerve factor.

According to one embodiment of this mode, the nerve factor comprises atleast one substance associated with at least one of a nerve fiber or acellular structure associated with the nerve fiber.

In another embodiment, the nerve factor comprises a substance associatedwith a nerve fiber. According to one particularly beneficial embodiment,the substance is in particular associated with nociceptors.

In another more particular mode, the pain factor comprises a bloodvessel factor.

According to one embodiment of this mode, the blood vessel factorcomprises at least one of a blood vessel or a substance or structureassociated with the blood vessel.

In another embodiment of this mode, the blood vessel factor comprises asubstance or structure associated with microvessels.

According to another more particular mode, the pain factor comprises acellular factor.

According to one embodiment of this particular mode, the cellular factoris associated with a cell that produces at least one inflammatoryfactor.

In another embodiment, the cellular factor is associated with at leastone inflammatory factor.

In another embodiment, the cellular factor is associated with cellsactively producing inflammatory factors.

In another embodiment, the cellular factor is associated with aninflammatory cell of a type that is attracted to a second pain factor atthe location. According to one particular variation of this embodiment,the inflammatory cell comprises a leukocyte or macrophage.

According to another more particular mode, the pain factor comprises aninflammatory factor.

According to another mode, the pain factor comprises a cytokine.

According to another mode of the present aspect, the pain factorcomprises substance P or an analog or derivative or binding agent orantibody thereof.

According to another mode, the pain factor comprises CGRP or an analogor derivative or binding agent or antibody thereof.

According to another mode, the pain factor comprises receptor tyrosinekinase A (TrkA) or an analog or derivative thereof.

According to another mode, the pain factor comprises a TrkA bindingagent or antibody.

According to another mode, the pain factor comprises a TrkA receptor ora binding agent or antibody thereof.

According to another mode, the pain factor comprises nerve growth factor(NGF) or an analog or derivative thereof.

According to another mode, the pain factor comprises an NGF bindingagent or antibody.

According to another mode, the pain factor comprises an NGF antagonistor an analog or derivative thereof.

According to another mode, the pain factor comprises an NGF-antagonistbinding agent or anti-NGF antagonist antibody.

According to another mode, the pain factor comprises a nerve bindingagent or antibody or an analog or derivative thereof.

According to another mode, the pain factor comprises protein geneproduct 9.5 (PGP 9.5) or an analog or derivative or binding agent orantibody thereof.

According to another mode, the pain factor comprises SYN or an analog orderivative or binding agent or antibody thereof.

According to another mode, the pain factor comprises peripherin or ananalog or derivative or binding agent or antibody thereof.

According to another mode, the pain factor comprises Neurofilament 200kD (NF200) or an analog or derivative or binding agent or antibodythereof.

According to another mode, the pain factor comprises tissue necrosisfactor alpha (TNF-α or an analog or derivative or binding agent orantibody thereof.

According to another mode, the pain factor comprises a TNF-α blocker orbinding agent or antibody thereof.

According to another mode, the pain factor comprises macrophagemigration inhibitory factor (MIF or an analog or derivative or bindingagent or antibody thereof.

According to another mode, the pain factor comprises infliximab, or ananalog or derivative thereof, or a binding agent or an antibody thereof.

According to another mode, the pain factor comprises PECAM or an analogor derivative or binding agent or antibody thereof.

According to another mode, the pain factor comprises CD34 or an analogor derivative or binding agent or antibody thereof.

According to another mode, the pain factor comprises vascular celladhesion molecule-1 (VCAM-1) or an analog or derivative or binding agentor antibody thereof.

According to another mode, the pain factor comprises an interleukin oran analog or derivative or binding agent or antibody thereof.

According to one embodiment of this mode, the interleukin comprises IL-1or an analog or derivative or binding agent or antibody thereof.

According to another embodiment, the interleukin comprises IL-6 or ananalog or derivative or binding agent or antibody thereof.

According to another embodiment, the interleukin comprises IL-8 or ananalog or derivative or binding agent or antibody thereof.

According to another mode of the present aspect, the pain factorcomprises prostaglandin E2 (PGE₂) or an analog or derivative or bindingagent or antibody thereof.

According to another mode, the pain factor comprises a factor associatedwith pH in tissue or a binding agent or an antibody thereof.

According to one embodiment of this mode, the labeled pain factor isindicative of a relatively low pH below a predetermined threshold at thelocation.

According to another mode, the pain factor comprises a factor associatedwith pO2 in tissue or a binding agent or an antibody thereof.

In one embodiment according to this mode, the labeled pain factor isindicative of a relatively low pO2 at the location.

According to another mode, the pain factor comprises glial fibrillaryacidic protein (GFAP) or an analog or derivative or binding agent orantibody thereof.

According to another mode, the pain factor comprises synuclein (SYN) oran analog or derivative or binding agent or antibody thereof.

According to another mode of the present aspect, the targeted labelcomprises at least one of a nerve factor, a blood vessel factor, acellular factor, an inflammatory factor, or an antibody thereof.

According to one embodiment of this mode, the targeted label comprises anerve factor or a binding agent or an antibody thereof.

In one variation according to this embodiment, the nerve factorcomprises at least one substance associated with at least one of a nervefiber or a cellular structure associated with the nerve fiber or anantibody thereof.

In another variation, the nerve factor comprises a substance associatedwith a nerve fiber or a binding agent or an antibody thereof.

In another embodiment, the targeted label comprises a blood vesselfactor or a binding agent or an antibody thereof.

In one variation of this embodiment, the blood vessel factor comprises asubstance associated with a structure of a blood vessel or a bindingagent or an antibody thereof.

In another variation, the blood vessel factor comprises a substanceassociated with a structure of a microvessel or a binding agent or anantibody thereof.

According to another embodiment, the targeted label comprises a cellularfactor or a binding agent or an antibody thereof.

In one variation, the cellular factor is associated with a cell thatproduces at least one inflammatory factor, or a binding agent or anantibody thereof.

In another variation, the cellular factor is associated with at leastone inflammatory factor or a binding agent or an antibody thereof.

In another variation, the cellular factor is associated with anintervertebral disc cell that is actively producing inflammatoryfactors, or a binding agent or an antibody thereof.

In another variation, the cellular factor is associated with aninflammatory cell of a type that is attracted to the pain factor at thelocation, or a binding agent or an antibody thereof.

According to one feature of this variation, the inflammatory cellcomprises a leukocyte, or a binding agent or an antibody thereof.

According to another embodiment, the targeted label comprises aninflammatory factor, or a binding agent or an antibody thereof.

In one variation of this embodiment, the inflammatory factor comprises acytokine, or an analog or derivative thereof, or a binding agent or anantibody thereof.

According to another mode of the present aspect, the targeted labelcomprises a binding agent or antibody to substance P.

According to another mode, the targeted label comprises a binding agentor antibody to calcitonin gene-related peptide (CGRP).

According to another mode, the targeted label comprises a TrkA antibodyor binding agent.

According to another mode, the targeted label comprises nerve growthfactor (NGF), or an analog or derivative thereof.

According to another mode, the targeted label comprises a NGF bindingagent or an anti-NGF antibody.

According to another mode, the targeted label comprises a NGF antagonistor a binding agent or an antibody thereof.

According to another mode, the targeted label comprises an anti-NGFantagonist antibody or binding agent.

According to another mode, the targeted label comprises a nerve antibodyor binding agent.

According to another mode, the targeted label comprises PGP 9.5, or ananalog or derivative thereof, or a binding agent or an antibody thereof.

According to another mode, the targeted label comprises a binding agentor antibody to peripherin.

According to another mode, the targeted label comprises Neurofilament200 kD (NF200), or an analog or derivative thereof, or a binding agentor an antibody thereof.

According to another mode, the targeted label comprises TNF-α, or ananalog or derivative thereof, or a binding agent or an antibody thereof.

According to another mode, the targeted label comprises a TNF-α blocker.

According to another mode, the targeted label comprises infliximab, oran analog or derivative thereof, or a binding agent or an antibodythereof.

According to another mode, the targeted label comprises a PECAM bindingagent or antibody.

According to another mode, the targeted label comprises a binding agentor antibody to CD34.

According to another mode, the targeted label comprises an interleukinbinding agent or antibody.

In one embodiment of this mode, the interleukin binding agent orantibody comprises an IL-1 binding agent or antibody.

In another embodiment of this mode, the interleukin binding agent orantibody comprises an IL-6 binding agent or antibody.

In another embodiment of this mode, the interleukin binding agent orantibody comprises an IL-8 binding agent or antibody.

According to another mode of the present aspect, the targeted labelcomprises a binding agent or antibody to PGE₂.

According to another mode, the targeted label comprises a binding agentor antibody to MIF.

According to another mode, the targeted label comprises an antibody orbinding agent to a factor associated with pH in tissue.

According to one embodiment of this mode, the labeled pain factor isindicative of a relatively low pH below a predetermined threshold at thelocation.

According to another mode, the targeted label comprises an antibody orbinding agent to a factor associated with pO2 in tissue.

According to one embodiment of this mode, the labeled pain factor isindicative of a relatively low pO2 at the location.

According to another mode, the targeted label comprises a radioactivematerial.

According to one embodiment of this mode, the targeted label comprises aradio-labeled TNF-α antibody, or an analog or derivative thereof.

According to another embodiment, the targeted label comprisesradiolabeled iodine. In one variation of this embodiment, theradiolabeled iodine comprises I-125.

According to another mode, the targeted label comprises a nanoparticle.

According to another mode, the targeted label comprises gold.

According to another mode, the targeted label comprises iron oxide.

According to another mode, the targeted label comprises gadolinium.

According to another mode of the present aspect, the method furtherincludes imaging the labeled pain factor using an imaging tool thatcomprises a phosphor imaging plate.

According to another mode, the method includes imaging the labeled painfactor using MRI.

According to another mode, a first binding agent is delivered into thebody that is adapted to bind to a first pain factor. The targeted labelis delivered into the patient's body after the first binding agent isbound to the first pain factor. The targeted label is adapted to bind toa site located on the bound combination of the first binding agent andthe first pain factor.

According to one embodiment, the first binding agent comprises abi-specific antibody with a first binding site adapted to bind to thefirst pain factor and a second binding site adapted to bind to thetargeted label.

According to another mode, the targeted label comprises a cell bound toan antibody having an exposed binding site that is adapted to bind tothe pain factor.

According to another mode, the method further includes conducting atherapeutic procedure in a substantially localized manner to thelocation where the targeted labeled pain factor is locally imaged.

In one embodiment of this mode, the therapeutic procedure is adapted tosubstantially alleviate generation or transmission of pain at thelocation.

According to another embodiment, the therapeutic procedure is adapted tosubstantially ablate at least one nerve at the location.

In another embodiment, the therapeutic procedure comprises delivering atleast one therapeutic chemical in a substantially localized manner tothe location.

In another embodiment, the therapeutic procedure comprises delivering atherapeutic dose of energy in a substantially localized manner to thelocation.

In one variation of this embodiment, the therapeutic procedure furthercomprises ablating at least one nerve at the location with thetherapeutic dose of energy.

In another variation, the therapeutic procedure further comprisesdelivering ultrasound energy to the location. In a further variation,the method further includes delivering the ultrasound energy in adirected manner locally into the location from a second location. Instill a further variation, the second location is outside of thepatient, and the ultrasound energy is delivered via high intensityfocused ultrasound (HIFU) that is adapted to focus the ultrasound energyto the location. In yet another variation, the second location isadjacent to the location within the patient, and the ultrasound energyis delivered via a directional ultrasound probe. In still a furtherfeature of this variation, the second location is adjacent to anintervertebral disc and the location receiving the directionalultrasound therapy is within the intervertebral disc.

According to another variation of the present embodiment, thetherapeutic dose of energy comprises thermal energy.

According to another variation, the therapeutic dose of energy compriseselectrical energy. In one further variation, the method involvesdelivering the electrical energy via a radiofrequency (RF) probe.

According to another variation, the therapeutic dose of energy comprisesmicrowave energy.

According to another variation, the therapeutic dose of energy compriseslight energy.

According to another mode of the present aspect, the location comprisesat least a portion of an intervertebral disc.

According to another mode, the location comprises a region of tissuelocated within only a portion that is equal to less than an entirecircumference of an intervertebral disc.

In one embodiment of this mode, the portion comprises a region of tissuelocated within less than or equal to one-half of the circumference ofthe intervertebral disc.

In one variation of this embodiment, the portion comprises a region oftissue located within less than or equal to one-quarter of acircumference of the intervertebral disc.

According to another mode of the present aspect of the invention, thelocation comprises an end-plate associated with a vertebral body.

According to another mode, the location comprises a facet joint.

The method of the present aspect according to another mode includesdelivering the targeted label in a localized manner to the location.

One embodiment of this mode further includes injecting the targetedlabel into a region of tissue associated with the location using a localinjection assembly.

Another embodiment includes delivering the targeted label systemicallyto the patient.

One further embodiment includes injecting the targeted label into thepatient's systemic blood circulation.

Another further embodiment includes delivering the targeted label intothe patient's gastrointestinal system.

Another mode includes artificially labeling the pain factor at multiplesaid locations by binding the pain factor with the targeted labeldelivered into the patient. The labeled pain factor is then imaged withan imaging tool adapted to image at least one of the targeted label orthe labeled pain factor and in a manner sufficient to differentiate afirst concentration of the labeled pain factor at the multiple saidlocations versus a second concentration of the labeled pain factor intissue adjacent to the multiple said locations.

According to one embodiment of this mode, the method further includesconducting at least one therapeutic procedure in a substantiallylocalized manner to each of the locations where the targeted labeledpain factor is locally and selectively imaged.

According to another mode of this present aspect, the pain factorcomprises MIF or a binding agent or antibody thereof.

According to another mode of this aspect, the targeted agent comprisesan MIF binding agent or antibody.

According to another mode of the present aspect, the targeted agentcomprises a nanoparticle.

According to another mode of the present aspect, the targeted agentcomprises at least one of gold or iron oxide.

According to another mode of the present aspect, the targeted agentcomprises an MRI contrast agent.

According to one embodiment of the preceding mode, the MRI contrastagent comprises gadolinium.

According to another embodiment of the present mode, the method furthercomprises MRI imaging an area of increased concentration of the MRIcontrast agent bound to the pain factor.

According to another mode of the present aspect, the targeted agentcomprises an ultrasound contrast agent.

According to one embodiment of this mode, the method further comprisesultrasonically imaging an area of increased concentration of theultrasound contrast agent bound to the pain factor.

According to another mode of the present aspect, the targeted agentcomprises a radiographic contrast agent.

According to one embodiment of this mode, the method further comprisesimaging an area of increased concentration of the radiographic contrastagent bound to the pain factor using X-ray.

According to another mode of the present aspect, the method furthercomprises imaging a location of the targeted agent bound to the painfactor in a manner allowing for enhanced localized therapy to thelocation.

According to another mode of the present aspect, the method furthercomprises delivering the targeted agent into the patient via thepatient's respiratory system.

Another aspect of the invention involves a system for treating pain at alocation within a body of a patient. This aspect includes a targetedagent that comprises a targeted label that is adapted to bind to andlabel a pain factor associated with a source of pain at the location.Also included is a delivery assembly that is adapted to deliver thetargeted label into the patient. An imaging system also included in thesystem is adapted to image at least one of the targeted label or thelabeled pain factor and in a manner sufficient to selectivelydifferentiate a first concentration of the labeled pain factor at thelocation versus a second concentration of the labeled pain factor intissue adjacent to the location. A therapeutic device assembly is alsoincluded, and is adapted to provide therapy in a substantially localizedmanner that is substantially isolated to the location.

According to one mode of this aspect, the targeted label is adapted tobind and label a pain factor associated musculoskeletal joint pain, andthe location is associated with at least one musculoskeletal joint.

According to one embodiment, the therapeutic device assembly comprisesan energy delivery assembly that is adapted to deliver a therapeuticdose of energy in a substantially localized manner that is substantiallyisolated to the location associated with the musculoskeletal joint.

According to one further embodiment, the energy delivery assembly isadapted to be delivered into the patient to a position at or adjacent tothe location.

According to another further embodiment, an introducer is provided inthe system and is adapted to deliver the energy delivery assembly to thelocation.

In one variation of this embodiment, the introducer comprises a needleassembly. This may provide the additional feature in that the needleassembly is adapted to be advanced through bone and to deliver thetherapeutic device assembly to a position within the bone. According toanother further feature, the therapeutic device assembly may be adaptedto ablate an intraosseous nerve within the bone and that is associatedwith pain related to the labeled pain factor visualized at the location.In another further beneficial feature, the needle assembly is adapted tobe advanced through bone of a vertebral body and to deliver thetherapeutic device assembly to a position within the vertebral bodyassociated with a basivertebral nerve, and the therapeutic deviceassembly is adapted to ablate the basivertebral nerve from the position.

According to another mode of the present aspect, the therapeutic deviceassembly comprises a radiofrequency (RF) current ablation assembly.

In one embodiment, the RF current ablation assembly comprises a firstelectrode and a second electrode adapted to be positioned at first andsecond positions adapted to straddle at least a portion of thebasivertebral nerve. The RF current ablation assembly is adapted todeliver the RF current between the first and second electrodessufficient to ablate nerve tissue between the first and secondpositions.

According to one variation of this embodiment, the RF current ablationassembly comprises a delivery probe with an elongated body that carriesthe first and second electrodes in a bipolar lead assembly arrangement.

According to another mode of the present embodiment, the targeted labelis adapted to bind and label a pain factor comprising at least one of anerve factor, a blood vessel factor, a cellular factor, an inflammatoryfactor, or an antibody thereof.

It is to be appreciated that further more detailed particularlybeneficial modes provided hereunder are contemplated with respect to thepresent aspect described. In particular, further modes of the presentaspect include the various beneficial examples for pain factors andtargeted labels described for use under the method aspect of theinvention described above.

According to one further mode of the present aspect, the targeted labelis adapted to selectively bind and label a pain factor that comprises atleast one of Substance P, CGRP, trkA, NGF, an NGF antagonist, PGP 9.5,SYN, peripherin, Neurofilament 200 kD (NF200), PECAM, CD34, GFAP, aninterleukin, a leukocyte, a cytokine, TNF-α, MIF, an analog orderivative thereof, or a binding agent or antibody thereof.

According to another mode of the present aspect, the targeted labelcomprises a binding agent or antibody of at least one of Substance P,CGRP, trkA, NGF, an NGF antagonist, PGP 9.5, SYN, peripherin,Neurofilament 200 kD (NF200), PECAM, CD34, GFAP for endothelial cells,an interleukin, a leukocyte, a cytokine, TNF-α or MIF, or comprises NGF,NF200, PGP 9.5, or an analog or derivative thereof.

According to another mode of the present aspect, the targeted label isadapted to bind and label TNF-α or a binding agent or an antibodythereof.

According to another mode of the present aspect, the targeted labelcomprises a labeled TNF-α antibody or binding agent.

According to another mode of the present aspect, the targeted labelcomprises infliximab, or an analog or derivative thereof, or a bindingagent or antibody thereof.

According to another mode of the present aspect, the targeted labelcomprises a radioactive material. According to one embodiment of thismode, the targeted label comprises a radio-labeled TNF-α antibody, or ananalog or derivative thereof. According to another embodiment of thismode, the targeted label comprises radiolabeled iodine. According to onevariation of this embodiment, the radiolabeled iodine comprises 1-125.

According to another mode, the system further includes an imaging toolthat is adapted to image the labeled pain factor in a manner sufficientto differentiate a first concentration at the location associated withpain versus a second concentration at a second location adjacent to thelocation and associated with less pain that at the location.

According to another mode of the present aspect, the pain factorcomprises MIF or a binding agent or antibody thereof. According toanother mode, the targeted agent comprises an MIF binding agent orantibody. According to still another mode, the targeted agent comprisesa nanoparticle. According to yet still another mode, the targeted agentcomprises at least one of gold or iron oxide.

According to another mode of the present aspect, the targeted agentcomprises an MRI contrast agent. According to one embodiment of thismode, the MRI contrast agent comprises gadolinium. According to anotherembodiment, the system further comprises an MRI system configured forMRI imaging an area of increased concentration of the MRI contrast agentbound to the pain factor.

According to another mode of the present aspect, the targeted agentcomprises an ultrasound contrast agent. According to one embodiment ofthis mode, the system further comprises an ultrasound imaging systemconfigured for ultrasonically imaging an area of increased concentrationof the ultrasound contrast agent bound to the pain factor.

According to still another mode of the present aspect, the targetedagent comprises a radiographic contrast agent. In one embodiment of thismode, the system further comprises an X-ray imaging system configuredfor X-ray imaging an area of increased concentration of the radiographiccontrast agent bound to the pain factor.

Another aspect of the invention is a method for imaging and identifyinga localized, active source of pain at a location associated with aregion of tissue in a patient, such as in particular beneficial furthermodes a skeletal joint in a patient, and in still further beneficialmore detailed modes spinal joints in a patient. This method includesdelivering a substantially targeted label into the patient that isadapted to differentially bind to and label a pain factor. A pain factorthat is resident at the location is artificially labeled by binding thepain factor with the targeted label delivered into the patient. Thelabeled pain factor is imaged with an imaging tool adapted to image atleast one of the label or the labeled pain factor and in a mannersufficient to differentiate a first concentration of the labeled painfactor at the location versus a second concentration of the labeled painfactor in tissue adjacent to the location.

According to various modes of this aspect, the pain factor may berelated to at least one of a nerve fiber, a substance associated with anerve fiber, a blood vessel, a substance associated with a blood vessel,a cell actively producing at least one inflammatory factor, a cellattracted to inflammation or other pain factors, or a chemo-inflammatoryfactor, or a combination thereof.

Another aspect of the invention is a system for identifying orcharacterizing a property of tissue associated with a skeletal joint.Such aspect may further include any one or more of the various aspects,modes, embodiments, variations, or features herein shown or described,or combinations thereof.

According to one mode of this aspect, the system is adapted to provideinformation indicative of a degree of a property of at least a portionof an intervertebral disc.

Another aspect is a system for identifying or characterizing a propertyof tissue associated with a skeletal joint in a patient. This includeslabeling at least one of: pain factors, nerve factors, blood vesselfactors, cellular factors, or inflammation factors. Or, the system mayinclude a combination of one or more of the foregoing.

According to one mode of this aspect, the information is related to adegree of a property of at least a portion of an intervertebral disc.

Another aspect of the invention is a system for characterizing at leasta portion of an intervertebral disc with respect to a degree of aproperty of that disc, such as in particular related to pain ordegeneration. This system includes a labeled marker delivery system anda labeled marker imaging system. The labeled marker imaging systemprovides information that is useful to indicate at least in part thedegree of the property.

According to one further embodiment of the foregoing aspects and modes,the respective system is adapted to produce the information based oneither or both of an annular portion or a nucleus portion of theintervertebral disc.

According to another embodiment, the system is adapted to display ageographical representation related to the spatial concentration of thelabeled factor, and a portion of the geographical representationprovides the information.

According to another embodiment, the information is adapted todistinguish a degree of degradation of the disc. According to one highlybeneficial further embodiment, the information is adapted to distinguishas to the degree of degradation by reference to a Thompson scale.

According to another embodiment, the property comprises at least one ofpain, or at least one factor that correlates with pain.

According to another embodiment, the information is related to ratios ofconcentration of one or more pain factors.

According to another embodiment, the information is related to presenceof secondary or other indirect materials that generally, thoughindirectly, correlate well with presence of other more direct painfactors.

According to another embodiment, the information relates to at least onechemical constituent of an intervertebral disc.

According to another embodiment, the property comprises at least one ofa degree of dehydration of the disc, a degree of breakdown of aproteoglycan matrix of the disc, and a degree in a breakdown of acollagen matrix.

According to another embodiment, the system further includes aradiolabel imaging system that is adapted to produce the information.

Another aspect of the invention is a method for identifying orcharacterizing a property of tissue associated with a skeletal joint.One or more of the foregoing method aspects, modes, embodiments,variations, or features herein described, or combinations thereof, maybe employed to advance this method.

One further mode of this aspect further includes providing informationindicative of a degree of a property of at least a portion of anintervertebral disc.

Another aspect is a method for identifying or characterizing a propertyof tissue associated with a skeletal joint in a patient, and includes atleast one of the following steps: labeling a pain factor in the tissue;imaging the labeled pain factor in the tissue; comparing differentimaged regions having different concentrations of the labeled painfactor; identifying a location of increased presence of pain factorsbased upon the comparison; and treating the location with localtreatment modality based upon the identification. Or a combination ofone or more of the foregoing may be used.

One mode of this aspect includes determining a degree of a property ofat least a portion of an intervertebral disc based upon the information.

Another aspect of the invention is a method for characterizing at leasta portion of an intervertebral disc with respect to a degree of aproperty thereof, and includes capturing a signal related to the portionusing a signal imaging system. The signal imaging system providesinformation that indicates at least in part the degree of the property.

According to one embodiment of the various method aspects and modes justdescribed, the information produced is based on either or both of anannular portion or a nucleus portion of the intervertebral disc.

In another embodiment, a curve is displayed that is related to thepresence of the labeled pain factor, and wherein a portion of the curveprovides the information.

Another embodiment includes distinguishing a degree of degradation ofthe disc based upon the information. A still further embodiment includesdistinguishing the degree of degradation of the disc in relation to aThompson grade based upon the information.

Another embodiment includes correlating the disc with degree of pain, orat least one factor that correlates with pain, based upon theinformation.

According to another embodiment, the information is related to a ratioof magnitude of a signal imaged that corresponds with the amount oflabeled pain factor in a given area or volume of tissue.

According to another embodiment, the information is related to acytokine, a precursor material thereof, an analog or derivative thereof,or a metabolite or degradation product thereof.

According to another embodiment, the information relates to at least onechemical constituent of an intervertebral disc.

According to another embodiment, the property relates to at least one ofa degree of dehydration of the disc, a degree of breakdown of aproteoglycan matrix of the disc, and a degree in a breakdown of acollagen matrix.

Another embodiment includes producing the information at least in partusing a radiation imaging system.

Another aspect is a method for preparing a system for performing amedical procedure on a patient, comprising: diagnosing the patient withpain; and based upon the diagnosis, preparing a volume of a targetedagent for delivery into the patient. The prepared volume of targetedagent is configured to differentially bind to a pain factor associatedwith the pain in a manner adapted to enhance at least one of (i)diagnostic localization of the pain and (ii) selective tissue therapy inan area associated with the bound pain factor in response to a deliveredenergy to the area.

According to one mode of this aspect, the pain factor comprises MIF or abinding agent or antibody thereof.

According to another mode of this aspect, the targeted agent comprisesan MIF binding agent or antibody.

According to another mode of the present aspect, the targeted agentcomprises a nanoparticle.

According to another mode of the present aspect, the targeted agentcomprises at least one of gold or iron oxide.

According to another mode of the present aspect, the targeted agentcomprises an MRI contrast agent.

According to one embodiment of the preceding mode, the MRI contrastagent comprises gadolinium.

According to another embodiment of the present mode, the method furthercomprises MRI imaging an area of increased concentration of the MRIcontrast agent bound to the pain factor.

According to another mode of the present aspect, the targeted agentcomprises an ultrasound contrast agent.

According to one embodiment of this mode, the method further comprisesultrasonically imaging an area of increased concentration of theultrasound contrast agent bound to the pain factor.

According to another mode of the present aspect, the targeted agentcomprises a radiographic contrast agent.

According to one embodiment of this mode, the method further comprisesimaging an area of increased concentration of the radiographic contrastagent bound to the pain factor using X-ray.

According to another mode of the present aspect, the method furthercomprises imaging a location of the targeted agent bound to the painfactor in a manner allowing for enhanced localized therapy to thelocation.

According to another mode of the present aspect, the method furthercomprises delivering the targeted agent into the patient via thepatient's respiratory system.

Another aspect is a system for performing a medical procedure on apatient, comprising: a therapeutic volume of a targeted agent preparedfor delivery into a patient diagnosed with pain and that is configuredto differentially bind to a pain factor associated with the pain in amanner adapted to enhance at least one of (i) diagnostic localization ofthe pain and (ii) selective tissue therapy to a location containing thebound pain factor in response to a delivered energy to an areacontaining the location.

According to one mode of the present aspect, the pain factor comprisesMIF or a binding agent or antibody thereof. According to another mode,the targeted agent comprises an MIF binding agent or antibody. Accordingto still another mode, the targeted agent comprises a nanoparticle.According to yet still another mode, the targeted agent comprises atleast one of gold or iron oxide.

According to another mode of the present aspect, the targeted agentcomprises an MRI contrast agent. According to one embodiment of thismode, the MRI contrast agent comprises gadolinium. According to anotherembodiment, the system further comprises an MRI system configured forMRI imaging an area of increased concentration of the MRI contrast agentbound to the pain factor.

According to another mode of the present aspect, the targeted agentcomprises an ultrasound contrast agent. According to one embodiment ofthis mode, the system further comprises an ultrasound imaging systemconfigured for ultrasonically imaging an area of increased concentrationof the ultrasound contrast agent bound to the pain factor.

According to still another mode of the present aspect, the targetedagent comprises a radiographic contrast agent. In one embodiment of thismode, the system further comprises an X-ray imaging system configuredfor X-ray imaging an area of increased concentration of the radiographiccontrast agent bound to the pain factor.

Another aspect is a method for selectively treating one or more tissueregions associated with pain in a patient, comprising delivering atargeted agent into the patient configured to differentially bind to apain factor associated with the pain; and allowing the deliveredtargeted agent to differentially bind to the pain factor so as to form adifferentially bound pain factor; and delivering energy into the patientin a manner that differentially treats the one or more regionsassociated with the differentially bound pain factor.

According to one mode of this aspect, the pain factor comprises MIF or abinding agent or antibody thereof.

According to another mode of this aspect, the targeted agent comprisesan MIF binding agent or antibody.

According to another mode of the present aspect, the targeted agentcomprises a nanoparticles.

According to another mode of the present aspect, the targeted agentcomprises at least one of gold or iron oxide.

According to another mode of the present aspect, the targeted agentcomprises an MRI contrast agent.

According to one embodiment of the preceding mode, the MRI contrastagent comprises gadolinium.

According to another embodiment of the present mode, the method furthercomprises MRI imaging an area of increased concentration of the MRIcontrast agent bound to the pain factor.

According to another mode of the present aspect, the targeted agentcomprises an ultrasound contrast agent.

According to one embodiment of this mode, the method further comprisesultrasonically imaging an area of increased concentration of theultrasound contrast agent bound to the pain factor.

According to another mode of the present aspect, the targeted agentcomprises a radiographic contrast agent.

According to one embodiment of this mode, the method further comprisesimaging an area of increased concentration of the radiographic contrastagent bound to the pain factor using X-ray.

According to another mode of the present aspect, the method furthercomprises imaging a location of the targeted agent bound to the painfactor in a manner allowing for enhanced localized therapy to thelocation.

According to another mode of the present aspect, the method furthercomprises delivering the targeted agent into the patient via thepatient's respiratory system.

Another aspect is a system for selectively treating one or more tissueregions associated with pain in a patient, comprising: a volume oftargeted agent; and an energy delivery system that is configured todeliver energy into the patient. The volume of targeted agent isconfigured for delivery into a patient and to differentially bind to apain factor associated with the pain in a manner such that tissueregions containing a first concentration of the differentially boundpain factor exhibit a differential and selective therapeutic response tothe delivered energy versus other regions with lower concentrations ofthe differentially bound pain factor.

According to one mode of the present aspect described immediately above,the pain factor comprises MIF or a binding agent or antibody thereof.According to another mode, the targeted agent comprises an MIF bindingagent or antibody. According to still another mode, the targeted agentcomprises a nanoparticle. According to yet still another mode, thetargeted agent comprises at least one of gold or iron oxide.

According to another mode of the present aspect, the targeted agentcomprises an MRI contrast agent. According to one embodiment of thismode, the MRI contrast agent comprises gadolinium. According to anotherembodiment, the system further comprises an MRI system configured forMRI imaging an area of increased concentration of the MRI contrast agentbound to the pain factor.

According to another mode of the present aspect, the targeted agentcomprises an ultrasound contrast agent. According to one embodiment ofthis mode, the system further comprises an ultrasound imaging systemconfigured for ultrasonically imaging an area of increased concentrationof the ultrasound contrast agent bound to the pain factor.

According to still another mode of the present aspect, the targetedagent comprises a radiographic contrast agent. In one embodiment of thismode, the system further comprises an X-ray imaging system configuredfor X-ray imaging an area of increased concentration of the radiographiccontrast agent bound to the pain factor.

Another aspect of the invention is a method of performing a medicalprocedure on a patient, comprising: delivering a material to a regionwithin a body of a patient; wherein the material has a preferentialbinding affinity to a pain factor located within the region sufficientto preferentially bind to the pain factor versus other structures withinthe region, and such that the material accumulates at a higherconcentration within a first portion of the region having a higheramount of the pain factor than other portions within the region; andafter delivering the material to the region, delivering energy to theregion in a manner that selectively treats the first portion versus theother portions and such that pain is reduced in the region.

According to one mode of the method just described, the materialcomprises a metal. In one embodiment of this mode, the materialcomprises gold. In another embodiment of this mode, the materialcomprises a nanoparticle. In still another embodiment, the materialcomprises a gold nanoparticle.

According to another mode of the present method aspect, the materialcomprises an antibody.

In another mode of this aspect, the material comprises an antibody and ametal associated with the antibody. According to one embodiment of thismode, the material comprises an antibody and a metal nanoparticleassociated with the antibody. In a further variation of this embodiment,the material comprises an antibody and a gold nanoparticle associatedwith the antibody.

According to another mode of the present method aspect, the regioncomprises a skeletal joint.

According to still another mode of the present method aspect, the regioncomprises at least a portion of a spine. In one embodiment of this mode,the first portion comprises at least one spinal joint level along thespine, and the other portions comprise at least one other spinal jointlevel along the spine. In another embodiment of this mode, the firstportion comprises a single spinal joint. In still another embodiment ofthis mode, the region comprises at least an area of a spinal joint. Inone variation of this embodiment, the first portion comprises at leastpart of an intervertebral disc. In another variation, the first portioncomprises at least part of a vertebral body. In still another variation,the first portion comprises at least part of a vertebral body endplate.In yet another further variation, the first portion comprises a facetjoint. In another variation, the first portion comprises a transverseprocess.

According to another mode of the present method aspect, the pain factorcomprises at least one of: a nerve factor, a blood vessel factor, amicrovessel factor, a cellular factor, an inflammatory factor, a cellthat produces at least one inflammatory factor, a cellular factorassociated with an intervertebral disc cell that is actively producinginflammatory factors, a cellular factor associated with an inflammatorycell of a type that is attracted to a second pain factor at thelocation, a leukocyte, a cytokine, substance P, CGRP, trkA, nerve growthfactor (NGF), an NGF receptor, an NGF antagonist, PGP 9.5, SYN,peripherin, Neurofilament 200 kD (NF200), TNF-α, a TNF-α blocker, aTNF-α receptor, infliximab, PECAM, CD34, GFAP, interleukin, IL-1, IL-6,IL-8, PGE-2, a factor associated with pH in tissue, a factor associatedwith pO2 in tissue, a binding agent or antibody thereof, a receptorthereof, an analog thereof, and a derivative thereof.

According to still another mode of the present method aspect, the methodfurther comprises imaging the region in a manner that sufficientlydifferentiates spatial relationships between different concentrations ofthe material so as to substantially identify the location of the firstportion relative to the other portions within the region.

According to one embodiment of this mode, the method further comprisesdelivering the energy principally to the first portion in asubstantially localized manner sufficient to differentially treat thefirst portion with the energy versus the other portions.

According to another mode of the present method aspect, the methodfurther comprises diagnosing the patient in a manner that identifies theregion as a painful region of the patient's body.

According to yet another mode of the present method aspect, the portionis not diagnosed to include cancer cells prior to conducting the medicalprocedure.

According to another mode of this present aspect, the pain factorcomprises MIF or a binding agent or antibody thereof.

According to another mode of this aspect, the targeted agent comprisesan MIF binding agent or antibody.

According to another mode of the present aspect, the targeted agentcomprises a nanoparticles.

According to another mode of the present aspect, the targeted agentcomprises at least one of gold or iron oxide.

According to another mode of the present aspect, the targeted agentcomprises an MRI contrast agent.

According to one embodiment of the preceding mode, the MRI contrastagent comprises gadolinium.

According to another embodiment of the present mode, the method furthercomprises MRI imaging an area of increased concentration of the MRIcontrast agent bound to the pain factor.

According to another mode of the present aspect, the targeted agentcomprises an ultrasound contrast agent.

According to one embodiment of this mode, the method further comprisesultrasonically imaging an area of increased concentration of theultrasound contrast agent bound to the pain factor.

According to another mode of the present aspect, the targeted agentcomprises a radiographic contrast agent.

According to one embodiment of this mode, the method further comprisesimaging an area of increased concentration of the radiographic contrastagent bound to the pain factor using X-ray.

According to another mode of the present aspect, the method furthercomprises imaging a location of the targeted agent bound to the painfactor in a manner allowing for enhanced localized therapy to thelocation.

According to another mode of the present aspect, the method furthercomprises delivering the targeted agent into the patient via thepatient's respiratory system.

Another aspect of the present invention is a system for treating apatient, comprising: a volume of material that comprises a metal;wherein the material exhibits a binding affinity to a pain factor suchthat when the material is delivered to a region within a body of apatient that includes the pain factor the material differentially bindsto the pain factor with more affinity than to other structures withinthe region, and such that the material accumulates at a higherconcentration within a first portion of the region having a higheramount of the pain factor than other portions within the region; and anenergy source that is adapted to deliver energy to the region in amanner that substantially locally treats the first portion versus theother portions.

According to one mode of this present aspect just described immediatelyabove, the metal comprises gold.

According to another mode of this present aspect, the metal comprises ametal nanoparticle.

According to another mode of this present aspect, the metal comprises agold nanoparticle.

According to another mode of this present aspect, the system furthercomprises an imaging system that is adapted to image the material in amanner that is adapted to sufficiently differentiate spatialrelationships between different concentrations of the material so as toidentify the location of the first portion relative to the otherportions within the region.

According to still another mode of this present aspect, the material isadapted to preferentially bind to a pain factor that further comprises:a nerve factor, a blood vessel factor, a microvessel factor, a cellularfactor, an inflammatory factor, a cell that produces at least oneinflammatory factor, a cellular factor associated with an intervertebraldisc cell that is actively producing inflammatory factors, a cellularfactor associated with an inflammatory cell of a type that is attractedto a second pain factor at the location, a leukocyte, a cytokine,substance P, CGRP, trkA, nerve growth factor (NGF), an NGF receptor, anNGF antagonist, PGP 9.5, SYN, peripherin, Neurofilament 200 kD (NF200),TNF-α, a TNF-α blocker, a TNF-α receptor, infliximab, PECAM, CD34, GFAPfor endothelial cells, interleukin, IL-1, IL-6, IL-8, PGE-2, a factorassociated with pH in tissue, a factor associated with pO2 in tissue, abinding agent or an antibody thereof, a receptor thereof, an analogthereof, and a derivative thereof.

According to still another mode of this present aspect, the materialcomprises an antibody of at least one of the pain factors provided inthe immediately preceding mode.

According to another mode of the present aspect, the pain factorcomprises MIF or a binding agent or antibody thereof. According toanother mode, the targeted agent comprises an MIF binding agent orantibody. According to still another mode, the targeted agent comprisesa nanoparticle. According to yet still another mode, the targeted agentcomprises at least one of gold or iron oxide.

According to another mode of the present aspect, the targeted agentcomprises an MRI contrast agent. According to one embodiment of thismode, the MRI contrast agent comprises gadolinium. According to anotherembodiment, the system further comprises an MRI system configured forMRI imaging an area of increased concentration of the MRI contrast agentbound to the pain factor.

According to another mode of the present aspect, the targeted agentcomprises an ultrasound contrast agent. According to one embodiment ofthis mode, the system further comprises an ultrasound imaging systemconfigured for ultrasonically imaging an area of increased concentrationof the ultrasound contrast agent bound to the pain factor.

According to still another mode of the present aspect, the targetedagent comprises a radiographic contrast agent. In one embodiment of thismode, the system further comprises an X-ray imaging system configuredfor X-ray imaging an area of increased concentration of the radiographiccontrast agent bound to the pain factor.

Each aspect, mode, embodiment, variation, or feature herein described isconsidered independently beneficial without requiring combination withthe others. However, such further combinations and sub-combinationsthereof are also considered yet further beneficial independent aspectsinvention. For example, where particular modes, embodiments, variations,or features are herein described with respect to one aspect hereunder,it is to be appreciated by one of ordinary skill that such descriptionis further applicable to other aspects also described though suchparticular combination may not be specifically mentioned. In furtherexample, a more detailed description provided with respect to a methodaspect may provide information that is to be clearly combined as furtherdevelopment of a similar system-related aspect or description, or visaversa.

Further aspects of the invention will be brought out in the followingportions of the specification, wherein the detailed description is forthe purpose of fully disclosing preferred embodiments of the inventionwithout placing limitations thereon.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

The invention will be more fully understood by reference to thefollowing drawings which are for illustrative purposes only:

FIG. 1 shows a schematic of certain cascades associated withinflammation and pain.

FIGS. 2A-D show stained cross-sectioned histology slides indicatingpresence of certain factors associated with pain as follows, wherein “N”is nucleus pulposus, “A” is annulus fibrosus, and “G” designates growthplate.

FIG. 2A shows a mid-sagittal section of normal mouse-tail discdemonstrating TNF-alpha localization in periphery of nucleus pulposus(brown stain).

FIG. 2B shows a normal mouse disc wherein localization of TNF-alpha ispresent in the hypertrophic zone of the growth plate as generallyexpected.

FIG. 2C shows in the compressed disc wherein increased amounts ofTNF-alpha are apparent within the nucleus and inner annulus.

FIG. 2D shows increased TNF-alpha in the nucleus, inner annulus andirregularities in growth plate observed in compressed disc.

FIG. 3 shows a schematic view of a mouse 30 according to an experimentalmodel wherein the mouse tail 36 is injured by a fixture 40 forevaluating pain factors.

FIG. 4 shows an experimental set-up related to the mouse injury modelillustrated in FIG. 3, wherein a series of mice 30 are positioned forviewing their respective tails via a phosphor imaging plate 50.

FIG. 5 shows an image 60 taken from a phosphor imaging plate accordingto the set-up shown in FIG. 4 for four treatment mice and one controlmouse tail (located centrally in the figure).

FIG. 6 shows a schematic view of MAPK signaling pathways associated withcertain pain factors.

FIG. 7 shows a schematic view of a NF-κβ pathway associated with certainpain factors.

FIG. 8 shows a schematic view of a prostaglandin pathway associated withcertain pain factors.

DETAILED DESCRIPTION OF THE INVENTION

Referring more specifically to the drawings, for illustrative purposesthe present invention is embodied in the systems and methods generallyshown in or illustrated by reference to FIG. 1 through FIG. 8. It willbe appreciated that the apparatus may vary as to configuration and as todetails of the parts, and that the method may vary as to the specificsteps and sequence, without departing from the basic concepts asdisclosed herein.

Label Disc Features Associated with Pain

Discogenic pain is generally believed to be a multifactoral phenomenonin many cases. In particular, three illustrative factors are summarizedin varying levels of detail here as examples that are consideredcontributors in various ways to (or otherwise indicative of) thegeneration or transmission of discogenic pain. It is believed that theseillustrative factors frequently act as a co-existent combination, oftenacting simultaneously. These types of factors are summarized as follows.

One such factor type relates to the presence of nociceptors. Normally,intervertebral discs are substantially avascular and only sparselyinnervated at the outer margins of the disc annulus. These unmyelinated,substance P (SP) or calcitonin gene-related peptide (CGRP) containingfibers are typically unresponsive and termed silent nociceptors[Cavanaugh, 1996]. SP and CGRP are believed to be the sensorytransmitters of nociceptive information. As degeneration proceeds,nerves can follow microvessels and grow deeper into discs, which mayoccur for example either peripherally or via the endplate. This nerveand vessel in-growth is facilitated by degeneration-related decreases indisc pressure and proteoglycan content.

A second such factor type is generally embodied by the need for theintradiscal nociceptors to be sensitized, and thus generally involvesagents providing such sensitization. This can occur for example viacytokines, which are typically small, secreted proteins that mediate andregulate inflammation. Elevated levels of certain cytokines have beenmeasured in human discs, and are associated with degeneration and pain.Such major cytokines have been observed to include interleukin-1, -6,and -8, tissue necrosis factor-alpha (TNF-α), macrophage migrationinhibitory factor (MIF), and prostaglandin E2 (PGE₂). The source ofcytokines can be circulating inflammatory cells, such as for example inthe case of herniated discs, or disc cells, such as for example in thecase of contained disc degeneration. These pro-inflammatory stimuli cantrigger cells to initiate a number of catabolic programs meant tostimulate tissue repair and remodeling that includes production ofmatrix metalloproteinases 1, 9 and 13. During this wound healingprocess, cytokines are also often involved in stimulating angiogenesisand granulation tissue formation.

In one particular beneficial embodiment of the present invention,cytokines and/or their cell-surface receptors are imaged at sites ofinflammation in vivo using labeled markers, such as radiolabels. Inparticular beneficial examples, cytokines are tagged with one or more ofthe following, without limitation: iodine-123, iodine-125, iodine-131,technetium-99m, fluorine-18, or indium-111. In addition,positron-emitting radioisotopes (for example and without limitationfluorine-18) can be imaged using positron emission tomography (PET) orpositron emission tomography-computed tomography (PET-CT). Otherradiolabeled compounds can be imaged for example using single photonemission computerized tomography (SPECT).

It is also to be appreciated that MRI may be employed according tofurther embodiments for visualizing or observing accumulation or bindingof various labeled markers variously herein described, such as forexample in applying gadolinium as a marker tagged to or conjugated withcertain labels to be bound to pain factors. Moreover, nanoparticles suchas gold or iron oxide may be used as labels or markers to bind andthereafter be viewed or selectively targeted for therapy usingappropriate visualization or treatment modalities, respectively.

A third such factor related to discogenic back pain involves discdepressurization that leads to mechanical instability while a pre-stressin the annulus and interspinal ligaments is diminished. Depressurizationand instability, in turn, lead to abnormal internal disc stress that maystimulate nerves, leading to discogenic pain. Abnormal disc stress mayalso cause disc cells to be pro-inflammatory, compounding the adverseeffects of an abnormal mechanical environment.

Labeling and Imaging Nerve Factors

According to certain particular embodiments, one or more materialsassociated with nerves in or around intervertebral discs are labeledwith markers that are imaged for localization of pain. This is premisedin part on the presence of certain such factors as indicators that painmay originate or transmit in the area. These embodiments include,without limitation, labeling structures or substances associated withnerves themselves. Further detailed modes of this include labelingsubstances within nerves, such as in particular but without limitationsubstance P or “CGRP”. Other nerve fiber factors, substances orcomponents that may be labeled according to such further embodiment(s)include, without limitation: TRK-α; anti-TRK-α antibody; nerve growthfactor (NGF); anti-NGF antibody; NGF antagonist; anti-NGF antagonistantibody; PGP 9.5; SYN; peripherin; or other form of nerve antibodies orrelated materials in general. Other materials such as neurofilament 200kD (NF200) [Johnson, 2001; Ashton, 1994] may also be the target of suchlabeling and subsequent imaging.

As apparent from these highly beneficial illustrative embodiments justnoted immediately above (and elsewhere herein), endogenous substancessuch as TrkA or NGF may be targeted as the pain factor for labeling, orrelated antibodies or other substances having particular bindingaffinity or specificity to such resident materials may be bound to themin the area of pain and then thereafter provide the binding site fortargeted labels to be subsequently delivered. In this regard, it is tobe appreciated that various forms binding agents are broadlycontemplated hereunder this description, though they may not beparticularly antibodies affecting function of the target for binding.For example but without limitation, an antibody mimetic may be employedaccording to the present embodiments. Furthermore, various suchsubstances described hereunder as targeted pain factors may bethemselves labeled as markers and delivered to other targets. Forexample, NGF may be labeled and artificially delivered as the agent tomark TrkA as the targeted pain factor for imaging. In each of thesedifferent types of exemplary cases, the ultimate target for labeling viaa separately delivered agent (e.g. whether the target is an endogenousresident substance or an artificially delivered substance) is considereda “nerve factor” as a pain factor according to the present embodiments.

The following description provides further understanding of the role ofthese types of chemicals and other materials with respect to thesepresent embodiments. Further description of the benefits of variousparticular illustrative examples are also provided elsewhere herein fora further understanding.

The intervertebral disc is normally avascular and only sparselyinnervated at the outer layers of the annulus fibrosus and the vertebralendplate [Fagan, 2003]. The outer ⅓ of the posterior annulus is believedto be most typically innervated by the afferent fibers from thesinovertebral nerve, which is considered a ‘recurrent branch’ of theventral ramus of the spinal nerve at the same level [Nakamura, 1996].The ventral and lateral aspects of the annulus are believed to be mosttypically innervated by the dorsal root ganglion (DRG) [Aoki, 2004].Also, it has been reported that sensory fibers from upper level DRGs arebelieved to most typically innervate the dorsal portion of discs via theparavertebral sympathetic trunk [Ohtori, 2001].

The endplate is also suggested to be innervated by the basivertebralnerve, which as further suggested may be a branch of the sinovertebralnerve entering the vertebral body through the posterior neurovascularforamen [Antonacci, 1998].

Nerves usually accompany blood vessels, but can be found as isolatednerves in disc matrix. These non-vessel-associated fibers found in backpain patients have been observed to express growth-associated protein 43(GAP43) as well as SP [Freemont, 1997]. Small disc neurons contain CGRPand also express the high-affinity nerve growth factor (NGF) receptor,tyrosine kinase A (trkA)[Aoki, 2004]. Disc inflammation has beenobserved to cause an increase in CGRP positive neurons [Aoki, 2004]. Arecent study showed that NGF is expressed in microvascular blood vesselsin a painful lumbar disc, and that there are trkA (TRK-α) expressingnerve fibers adjacent to the vessels that enter painful discs primarilythrough the endplate [Freemont, 2002; Brown, 1997]. Along with nervesgrowing into degenerated discs are specialized nerve support cellstermed ‘glia’ or Schwann cells localized using glial fibrillary acidicprotein (GFAP) [Johnson, 2001].

Accordingly, various such materials may provide the requisite bindingaffinity or specificity to painful regions (or highly innervatedregions) to play the role as the labeled marker agent for delivery topain factor targets. Or, these materials may provide the particulartarget as the pain factor to be labeled with selectively bound markersaccording to various embodiments of the present invention. In oneparticular beneficial example, TrkA antibody (or other binding agent) islabeled and delivered as a marker for binding and visualization at alocation associated with pain. In another beneficial example, NGF itselfis labeled and delivered as a marker to itself bind to TrkA. In furtherembodiments, the resident quantities of these materials are treated asthe pain factors themselves for targeted labeling, e.g. using antibodiesor other agents with beneficial binding affinity and/or specificity tothese types of resident compounds in painful regions.

The following Published PCT Patent Applications are herein incorporatedin their entirety by reference thereto: WO 2004/032870; WO 2004/058184;WO 2004/073653; WO 2004/096122; and WO 2005/000194.

The various compositions and methods described in these incorporatedreferences may be adopted where appropriate to one of ordinary skill aslabel/marker vehicles and/or pain factor targets according to furtherembodiments of the various aspects and modes of the present inventionherein described. For example without limitation, NGF antagonists,anti-NGF antibodies, anti-NGF antagonist antibodies, and variouscombinations or blends of these, or analog or derivatives thereof, maybe so incorporated as further embodiments of the aspects hereindescribed. Moreover, additional compounds may also be included in theagent delivery scheme, or as additional targets for labeled markers,such as for example opioids, NSAID, or other molecules or drug agentsrelated to pain therapy.

Labeling and Imaging Blood Vessel Factors

Since blood vessels typically run along side and co-existent withnerves, factors related to blood vessels may also be labeled and imagedas indicia regarding vascularity itself, or as a measure of concomitantinnervation in an area. Such constitutes a further embodimentcontemplated hereunder, and described in some further detail as follows.In one regard, PECAM and/or CD34 [Freemont, 2002; Brown, 1997] may beappropriate targets as factors related to blood vessels and thusindicating their presence in a particular location or region. Anotherexample of an appropriate target includes GFAP for endothelial cells[Johnson, 2001]. Other microvessel-related factors are considered asincluded, though not specifically listed here, as would be apparent toone of ordinary skill based upon review of this disclosure and otheravailable information.

Labeling and Imaging Inflammatory Factors

According to still further embodiments contemplated hereunder,inflammatory factors themselves may be labeled with targeted markers andimaged as indicators of pain in a location or area. One exemplary typeof such factor includes cytokines, such as for example but withoutlimitation (though considered of particular benefit): tnf-a, or certaininterleukins such as IL-1, 6, or 8 (or other interleukins). Anotherexemplary pro-inflammatory factor includes MIF and PGE₂.

Other factors considered indicative of certain activities orenvironmental considerations believed linked to pain, and thusappropriate targets for labeling and imaging using targeted markers,include: pH (e.g. in particular marking low pH as indicator of pain; orO2 levels, e.g. in particular marking low O2 as indicator of pain).

Cytokines, in the present context, are generally described as small,secreted proteins that mediate and regulate inflammation. They generallyact over short distances, short times, and at very low concentrations.They typically function by binding to specific membrane receptors, whichoften then signal the cell via second messengers (discussed below) toalter gene expression. Responses to cytokines include increasing ordecreasing expression of membrane proteins (including cytokinereceptors), cell proliferation, and secretion of effector molecules.Cytokines may act on the cells that secrete them (autocrine action), onnearby cells (paracrine action), or in some instances on distance cells(endocrine action). It is common for different cells types to secretethe same cytokine or for a single cytokine to act on several differentcell types (pleiotropy). Cytokines are redundant in their activity, andare often produced in a cascade, as one cytokine stimulates its targetcells to make additional cytokines. Cytokines can also actsynergistically or antagonistically.

Elevated levels of certain cytokines have been measured in human discs,and have been associated with degeneration and pain. Among the majorcytokines found are, for example and without limitation: interleukin-1,-6, and -8, tissue necrosis factor-alpha (TNF-α), and prostaglandin E2(PGE₂)[Miyamoto, 2000; Ahn, 2002; Olmarker, 1998; Weiler, 2005]. Thesource of cytokines can be circulating inflammatory cells in the case ofherniated discs [Kawaguchi, 2002; Woertgen, 2000], or disc cells in thecase of contained disc degeneration [Burke, 2002].

For disc cells, inflammatory factor production may be stimulated forexample as part of several signaling cascades (described below), byfragments of degraded extracellular matrix, or matrix deformation (FIG.1). These exemplary pro-inflammatory stimuli can trigger cells toinitiate a number of catabolic programs meant to stimulate tissue repairand remodeling that includes production of matrix metalloproteinases 1,9 and 13 [Anderson, 2002]. During this wound healing process, cytokinesare also involved in stimulating angiogenesis and granulation tissueformation [Gillitzer, 2001].

IL-1 and TNF-α

IL-1b and TNF-α have been observed to demonstrate overlappingpro-inflammatory effects, activate common signaling cascades, and inducesimilar target genes (see ref in Faur). Effector cascades mediatinginflammatory responses to IL-1 and TNF-α include the mitogen-activatedprotein kinases (MAPK), NF-κβ and prostaglandin signal transductionpathways (shalom-barak). The signaling molecule nitric oxide may alsoform important component of the inflammatory cascade.

Imaging via labeling tissue necrosis factor-alpha (TNF-α) provides oneparticular beneficial example of marking for imaging a pro-inflammatorycytokine that can chemically hypersensitize the intervertebral disc andspinal nerve roots, thereby contributing to low back pain. Studies havebeen conducted that utilize immunohistochemistry to localize TNF-α inhistologic sections of normal and degenerated mouse-tail discs. Thesestudies suggest that the levels of TNF-α are increased aftercompression-induced degeneration of the intervertebral disc (FIGS.2A-D).

To demonstrate a TNF-α based localization modality of the presentinvention, compositions and methods have been developed that label TNF-αantibodies with I-125 so that variations in TNF-α content can be imagedin vivo. An experiment was conducted to observe and confirm thebeneficial use of this approach as follows. Mice such as mouse 30 shownin FIG. 3 were subjected to conditions that initiate tail-discdegeneration (FIG. 3), and were then injected intravenously with I-125labeled TNF-α antibody. These animals were then imaged with a phosphorimaging plate, such as plate 50 shown in FIG. 4. Use of this compositionand imaging methods demonstrated readily observed increased uptake inthe regions of the injured discs, such as seen in image 60 in FIG. 5wherein four injured tails are shown in 2-group sets on either side of acentrally located control tail in the image that was not injured thoughreceived similar labeled marker injection.

This particular experiment was performed using a particularradio-labeled TNF-α blocker, more specifically infliximab (Trade name“Remicade™” commercially available from Johnson & Johnson), anddemonstrates one exemplary embodiment adapted for beneficial useaccording to the present invention. While this particular modality isconsidered highly beneficial in the specific mode described, it is alsoexemplary of a number of broad aspects of the present invention that maybe illustrated by many alternative or combinatorial approaches that areherein contemplated.

In one regard, the present illustrative embodiment provides an exampleof using a therapeutic compound that actually provides some pain-relatedtherapy (e.g. TNF-α antibody or other form of blocker) that is also usedto image the location of the pain being treated (as the labeled marker,as conducted in the illustrative experiment, or targeted factor itself).This step may be followed by additionally treating the imaged regionthereafter with additional spacially localized or directed therapies.Examples include, without limitation, directed energy therapies such asthose elsewhere herein described, or further localized injection ofsimilar or other therapeutic compound(s)).

In another more specific regard, TNF-α blockers or antibodies arecontemplated as a class of therapeutic compounds beneficially adaptedfor use according to the invention, within which infliximab or Remicade™(or analogs or derivatives thereof) is used in a particular beneficialembodiment as just described. These provide the benefit of selectiveuptake at nerve endings where pain may be occurring, and thus aparticular beneficial target agent for labeling to image pain. They alsoprovide the benefit of some therapeutic value to the pain itself.

Furthermore, it is to be appreciated that targeted agents, such asantibodies as herein described by way of example, may provide the labelfor imaging, or may take the form of the targeted factor (either byitself or by virtue of its conjugation or binding with a first residentfactor). In the later case, delivery of the first factor is thensubjected to subsequent labeling by delivery of a second agent as thelabeled marker (again either by its imagability itself or as bound,associated, or conjugated with the first delivered agent to the regionimaged).

MAPK Pathway

MAPKs form an intracellular signaling pathway built upon aself-propagating phosphorylation system (FIG. 6). Activation of MAPKsare one of the pivotal intracellular pathways triggered by cytokinereceptors (Shalom-berak). Three MAPK subgroups have been identified:extracellular signal regulated kinase (ERK); the Jun NH₂-terminalkinases (JNK); and p38 (geng, others). In chondrocytes, ERK activationoccurs in response to diverse stimuli, while JNK and p38 is only seen inresponse to IL-1 and TNF-α (Firestein, Iiancini): this signaling pathwayis thought responsible for cartilage degradation (geng). JNK and p38 arecollectively termed stress activated protein kinases (SAPKs). The signalis initiated by membrane-proximal small GTPases of the Rho family,activation of MLK, and phosphorylation and activation of MKK3/6 that inturn phosphorylates and activates p38. Faur).

One important endpoint of MAPK activation is the production of thephosphorylated active activator protein 1 (AP-1) transcription factor(heterodimer of c-Jun and c-Fos), which in turn, can influencechondrocyte collagenase activity (mengshol, Ferreria refs). AP-1 plays acentral role in the transcriptional regulation of many MMP genesincluding collagenase and stromelysin (mengshol refs, Firestein).Similarly, MIF activates the MAPK pathway and AP-1 leading to cellproliferation, and PGE₂ production, which eventually promotesmonocyte/macrophage activation. Certain published data suggests that MIFis in particular upregulated under conditions of chronic emotionalstress and can potentiate elevated levels of other inflammatory factorssuch as for example those examples herein described. Accordingly,labeling MIF provides yet a further embodiment of the various presentaspects.

JNK and p38 are essential for IL-1 induction of mmp-13, while ERKpathway is not. p38 is essential for multiple inflammatory genes,including II-1, TNF-α, 11-6, stromelysin-1 (mmp-3) and mmp-1(mengeshol).

It is to be appreciated that various such materials associated withpathways or molecular cascades associated with pain may provide thetarget for labeled markers and subsequent imaging as herein described,and various such materials are provided here as beneficial exampleswhich, though of particular value, are also not intended to limit broadaspects contemplated hereunder. In addition, such otherwise indigenousmaterials may also demonstrate selective uptake in tissues associatedwith pain. In such case, these otherwise indigenous materials (orsynthetic or other biologic constructs similar to them, such as analogsor derivatives thereof) may also be harnessed and labeled for deliveryas the labeled marker. Moreover, due to their selective uptake,particular accumulated concentrations of certain molecules in areas ofpain also render them viable targets as the pain factors themselves forlabeling with labeled markers that bind to them.

NF-κβ Pathway

In addition to the MAPK induction, IL-1 and TNF-α activate NF-κβ. NF-κβis a transcription factor that exists in a latent form in the cytoplasmof unstimulated cells and is composed of a transcriptionally activedimer (p65 and p50) bound to an inhibitor protein (|κβ) (Bowie,Magnani). NF-κβ is activated by a large number of different signals thatinclude similar cell stress signals that activate SAPKs. IL-1 and TNF-αtrigger the phosphorylation and degradation of |κβ, resulting in therelease of NF-κβ to enter the nucleus (refs in Shalom; Baeuerle). NF-κβactivation occurs through a cascade starting with NF-κβ-inducing kinase(NIK), which then phosphorylates and activates the inhibitor of NF-κβ(|κβ) kinases. Phosphorylation of |κβ results in ubiquitination anddegradation of |κβ inhibitory subunit, allowing NF-κβ to translocate tothe nucleus where it acts as a transcription factor and regulates itstarget genes, which include collagenase (MMP-1; Barchowsky) (Mengshol,magnani) and COX-2 (Mifflin). FIG. 7 shows certain further details ofthis cascade and relationship between components.

Prostaglandin Pathway

Eicosanoids are signaling molecules that act in an autocrine fashion.Pro-inflammatory stimuli can lead to increased phospholipid-derivedeicosanoid synthesis that involves a cascade of three enzyme reactions(FIG. 8). First, arachidonic acid (AA) is liberated from itsphospholipid storage sites by phospholipase A2 (PLA2). The nextrate-limiting step is conversion of AA to prostaglandin H2 bycyclooxgenase (COX).

The prostaglandin pathway is stimulated by IL-1b. This cytokineincreases the activity of PLA2 and induces COX-2 gene expression bybinding to a specific cell-surface receptor (IL-1RI) that ultimatelyleads to increases in COX-2 promoter activity via the NF-κβ pathway(Faur refs, geng). In chondrocytes, COX activity is not increased byTNF-α. Rather, TNF-α can amplify COX activity in IL-1 stimulated cells.(Berenbaum).

Prostaglandin E2 (PGE₂) stimulates the catabolism of chondrocytes,having both anti-proliferative and pro-apoptotic effects (berenbaum ref,also goldring ref in Iiancici). An increase in PGE₂ may therefore tipthe balance toward catabolism.

Nitric Oxide

Nitric oxide (NO) is a small signaling molecule that is part of thecatabolic program in chondrocytes induced by IL-1 and TNF-α (Lotz;Goldring). It is produced within the cell by the inducible isoform of NOsynthase (iNOS), and then passes readily through the cell membrane toaffect neighboring cells. Because it has a short half-life (5 to 10seconds) it acts only locally, yet it plays an important role in thepathophysiology of arthritic disease (Ferreira Mendes). It has beenshown to: induce apoptosis (by stimulating release of cytochrome c frommitochondria) and inflammation (by activating COX and PLA2 (Vassalle,clancey)); suppress collagen and proteoglycan synthesis; and upregulateMMP synthesis (Scheurwegh).

IL-1 and TNF-α increase the gene expression and synthesis of iNOS,through the transcription factors NF-κβ and AP-1. Activation of NF-κβ isan essential step for iNOS induction (see Mendes refs). Also, there issome evidence that the MAPK p38 may be involved in the activation ofNF-κβ and subsequent iNOS expression, since p38 is reported to berequired for IL-1-induced iNOS expression in chondrocytes (Mendes).

Labeling/Imaging Cellular Factors Associated with Inflammation

Cells that produce or are associated with inflammatory factors can alsobe labeled with targeted markers and thereafter imaged as an indicatorthat pain exists in the area. For example, disc cells that are activelysynthesizing inflammatory factors may be labeled as such (or componentsthereof may be labeled). Inflammatory cells that are attracted topainful discs, such as for example leukocytes, may be labeled and imagedfor this purpose.

The following articles are herein incorporated in their entirety byreference thereto.

-   1. Haro H, Crawford, H. J. Clin. Invest. 2000; 105:143-150.-   2. Mow V, Hayes, W. Basic Orthopaedic Biomechanics. In. New York:    Raven Press, 1991; 339-342.-   3. Thompson J P, Pearce, R. H., Schechter, M. T., Adams, M. E.,    Tsang, I. K., Bishop, P. B. Preliminary evaluation of a scheme for    grading the gross morphology of the human intervertebral disc. Spine    1990; 15:411-415.-   4. Iatridis J C, Setton, L. A., Weidenbaum, M., Mow, V. C.    Alterations in the mechanical behavior of the human lumbar nucleus    pulposus with degeneration and aging. In:Journal of orthopaedic    research, 1997; 318-322.-   5. Urban J P, McMullin, J. F. Swelling pressure of the    intervertebral disc: influence of proteoglycan and collagen    contents. Biorheology 1985; 1985.-   6. Beall P T, Amety, S. R. et al. States of Water in Biology: NMR    Data Handbook for Biomedical Applications. New York: Pergamon Press,    1984.-   7. Boos N, Boesch, C. Quantitative magnetic resonance imaging of the    lumbar spine: potential for investigations of water content and    biochemical composition. Spine 1995:2358-2366.-   8. Bottomley Pa., Foster, T. H. et al. A review of normal tissue    hydrogen NMR relaxation times and relaxation mechanisms from 1-100    MHz: dependence on tissue type, NMR frequency, temperature, species,    excision, and age. Medical Physics 1984:425-448.-   9. Lyons G, Eisenstein, S. M. et al. Biochemical changes in    intervertebral disc degeneration. Biochim Biophys Acta 1981:443-453.-   10. Majors A W, McDevitt, C. A. et al. A correlative analysis of T2,    ADC and MT ratios with water, hydroxyproline and GAG content in    excised human intervertebral disk. In:40th Annual Meeting    Orthopaedic Research Society. New Orleans, Louisiana: Orthopaedic    Research Society, 1994.-   11. Maroudas A. The Biology of the Intervertebral Disc. In: Ghosh P,    ed. The Biology of the Intervertebral Disc. Boca Raton: CRC Press,    1988; Ch. 9.-   12. Pearce R H, Grimmer, B. J. et al. Degeneration and the chemical    composition of the human lumbar intervertebral disc. Journal of    orthopaedic research 1987:198-205.-   13. Tertti M, Paajanen, H. et al. Disc degeneration in magnetic    resonance imaging: a comparative biochemical, histologic, and    radiologic study in cadaver spines. Spine 1991:629-634.-   14. Chui E, David C. Newitt, Mark R. Segal, Serena S. Hu, Jeffrey C.    Lotz, Sharmila Majumdar. Magnetic Resonance Imaging Measurement of    Relaxation and Water Diffusion in the Human Lumbar Intervertebral    Disc Under Compression In Vitro. Spine 2001; 26:E437-444.-   15. Gundry C R, Fritts, H. M. Magnetic resonance imaging of the    musculoskeletal system: Part 8. The spine. Clin Orthop Rel Res    1997:275-287.-   16. Gunzburg R PRea. A cadaveric study comparing discography,    magnetic resonance imaging, histology and mechanical behavior of the    human lumbar disc. Spine 1991:417-423.-   17. Modic Mont., Pavlicek, W. et al. Magnetic resonance imaging of    intervertebral disc disease: clinical and pulse sequence    considerations. Radiology 1984:103-111.-   18. Modic Mont., Masaryk, T. J. et al. Lumbar herniated disk disease    and canal stenosis: prospective evaluation by surface coil MR, CT    and myelography. ANJR 1986:709-717.-   19. Modic Mont., Masaryk, T. J. et al. Imaging of degenerative disc    disease. Radiology 1988:177-186.-   20. Sether La., Yu, S. et al. Intervertebral disk: Normal    age-related changes in MR signal intensity. Radiology 1990:385-388.-   21. Pfirrmann C, Metzdorf, A., Zanetti, M. Magnetic Resonance    Classification of Lumbar Intervertebral Disc Degeneration. Spine    2001; 26:1873-1878.-   22. Nieminen Mont., Rieppo, J., Silvennoinen, J. et al. Spatial    assessment of articular cartilage proteoglycans with    Gd-DTPA-enhanced T1 imaging. Magnetic Resonance in Medicine 2002;    48:640-648.-   23. Mosher T J, Dardzinski, B. J., Smith, M. B. Human articular    cartilage: influence of aging and early symptomatic degeneration on    the spatial variation of T2-preliminary findings at 3 T. Radiology    2000; 214:259-266.-   24. Boos N, Wallin, A., Boesch, C. H., Aebi, M. Quantitative MR    Imaging of diurnal water content variations in lumbar intervertebral    disc. In:38th Annual Meeting, Orthopeadic Research Society.    Washington, D.C.: The Orthopaedic Research Society, 1992; 165.-   25. Boos N, Wallin, A., Harms, S., Vock, P., Boesch, C. H., Aebi, M.    Tissue characterization of normal and herniated lumbar    intervertebral discs by quantitative MRI. In:39th Annual Meeting,    Orthopaedic Research Society. San Francisco, Calif.: Orthopaedic    Research Society, 1993; 417.-   26. Burstein D, Gray, M. L. et al. Diffusion of small solutes in    cartilage as measured by nuclear magnetic resonance (NMR)    spectroscopy and imaging. Journal of orthopaedic research    1993:465-478.-   27. Koh K, Kusaka, Y. et al. Self diffusion coefficient of water and    its anisotropic property in bovine intervertebral discs analyzed by    pulsed gradient NMR method. Orthop Trans 1992:483.-   28. Koh K, Kusaka, Y. et al. Self diffusion coefficient of water in    human intervertebral discs analyzed by pulsed gradient NMR method.    In:39th Annual Meeting Orthopaedic Research Society. San Francisco,    Calif., 1993.-   29. Abdulkarim J A, Dhingsa, R., Finlay, D. B. Magnetic Resonance    Imaging of the Cervical Spine: Frequency of Degenerative Changes in    the Intervertebral Disc with Relation to Age. Clinical Radiology    2003:980-984.-   30. Swanson M G, Vigneron D B, Tabatabai Z L, et al. Proton HR-MAS    spectroscopy and quantitative pathologic analysis of    MRI/3D-MRSI-targeted postsurgical prostate tissues. Magnetic    Resonance in Medicine 2003; 50:944-954.-   31. Schiller J, Naji, L., Huster, D., Kaufmann, J., Arnold, K. 1H    and 13C HR-MAS NMR investigations on native and enzymatically    digested bovine nasal cartilage. Magnetic Resonance Materials in    Physics, Biology and Medicine 2001:19-27.-   32. Carr H Y, Purcell, E. M. Effects of Diffusion on Free Precession    in Nuclear Magnetic Resonance Experiments. Physical Review 1954;    94:630-638.-   33. Kupce E. Applications of adiabatic pulses in biomolecular    nuclear magnetic resonance. In:Methods in Enzymology, 2001; 82-111.-   34. Mucci A, Schenetti, L., Volpi, N. 1H and 13C nuclear magnetic    resonance identification and characterization of components of    chondroitin sulfates of various origin. Carbohydrate Polymers    2000:37-45.-   35. Goupille P, Jayson, M. I., Valat, J. P., Freemont, A. J. Matrix    metalloproteinases: the clue to intervertebral disc degeneration?    Spine 1998; 23:1612-1626.-   36. Kang J D, Stefanovic-Racic, M., Mclntyre, L. A., Georgescu, H.    I., Evans, C. H. Toward a biochemical understanding of human    intervertebral disc degeneration and herniation. Contributions of    nitric oxide, interleukins, prostaglandin E2, and matrix    metalloproteinases. Spine 1997; 22:1065-1073.-   37. Weiler C, Nerlich, A. G., Zipperer, J., Bachmeier, B. E.,    Boos, N. 2002 SSE Award Competition in Basic Science: Expression of    major matrix metalloproteinases is associated with intervertebral    disc degradation and resorption. European Spine Journal    2002:308-320.-   38. Urban J P, Roberts, S., Ralphs, J. R. The Nucleus of the    Intervertebral Disc from Development to Degeneration. In: American    Zoologist, 2000; 53-61.-   39. Weidenbaum M, Foster, R. J., Best, B. A., Saed-Nejad, F.,    Nickoloff, E., Newhouse, J., Ratcliffe, A., Mow, V. C. Correlating    magnetic resonance imaging with the biochemical content of the    normal human intervertebral disc. Journal of orthopaedic research    1992; 10:552.-   40. EI-Sayed, I. H., Huang, X., EI-Sayed, M. A. “Surface Plasmon    Resonance Scattering and Absorption of anti-EGFR Antibody Conjugated    Gold Nanoparticles in Cancer Diagnostics: Applications in Oral    Cancer,” Nano Letters 2005 Vol. 5 No. 5 829-834.-   41. Herold, D. M., Das, I. J., Stobbe, C. C., lyer, R. V.,    Chapman, J. D., “Gold microspheres: a selective technique for    producing biologically effective dose enhancement,” Int. J. Radiat.    Biol. 2000, Vol. 76, No. 10, 1357-1364.

It is to be appreciated based upon the foregoing disclosure that painfactors are labeled and imaged in order to identify, with a usefuldegree of geographic specificity, active pain sites in and aroundskeletal joints. Such is considered highly beneficial in particular foruse in diagnosing the cause of pain, and understanding where and how totreat for pain relief, such as for example with local ablation or energydelivery systems, and/or local drug delivery.

Various terms have been used herein of a certain technical nature, andshould be given their standard technical meaning in the context of theparticular art to which this disclosure pertains, and in the context oftheir use in this description together with other accompanyingdisclosure, unless otherwise given a specific meaning hereunder.Notwithstanding the foregoing, it is understood that certain specificmaterials or types of materials are identified, whereas other similarmaterials or types of materials are also intended to be implicatedwithin the broad scope intended for the current invention. For example,“pain factors” are herein identified as playing a role in various of thepresent embodiments. Such terms are intended to mean any and allmaterials, whether structural, chemical, or otherwise, that have anassociation, either directly or indirectly, with pain such that bindingthem provides a vehicle to enhance diagnosis or therapy in relation tothe associated pain. In one particular example, factors related totransmitting pain signals along or between nerves are to be included.Or, factors that stimulate pain, such as “inflammatory” materials, areindicated. Materials related to other points in a chemical or biologicalcascade related to pain are also implicated, such as factors that relateto secondary or tertiary products or components of such pain generationor transmission process. If a factor is distinctly present (or absent)in a somewhat recognizable manner when and where pain is present, and ina different level or manner than when and where pain is not present,then it is considered a “pain factor” as herein described. This use ofthe term “factor” similarly applies in other contexts herein provided,such as for example “inflammatory factors”, “cellular factor(s)”, “nervefactors”, etc.

In another regard, it is also contemplated that, where certain specificexamples of chemicals or materials are herein provided, other relatedcompounds may be interposed in addition or in the alternative to suchspecified compound. For example, agents related to a certain materialmay be suitable substitutes and may include for example precursormaterials, such as a material that may be metabolized or otherwisealtered to produce the specified “factor” or “label” or other compoundor material referenced. Analogs or derivatives of the specified materialmay also be suitable in similar uses or preparations or systems. Thisincludes for example modified molecular forms of a specified materialthat retain the related binding or other activity of the specifiedmaterial so as to perform as herein described as a labeled pain factoror targeted label.

Moreover, use of a “marker” or “label” to tag or label a “factor” isgenerally herein described in fairly simple terms for the purpose ofproviding a general overall understanding of the broad aspectscontemplated hereunder. However, the actual steps and/or materials usedin order to achieve such “labeled pain factor” result may be moreextensive than herein described, though may be carried out by one ofordinary skilled in the art based upon review of this disclosure in itsentirety in combination with other available related information andthus further contemplated hereunder. For example, intermediary tagging,labeling, or binding may be beneficially used in order to achieve thelabeled marking necessary to provide differential imaging of the labeledresult in a useful manner.

In one further exemplary embodiment, bi-specific antibodies may be usedin such a manner as follows. One binding site of the bi-specificantibody provides a particular binding affinity for the pain factorbeing targeted, and thus differentially binds to that factor. However,this is done in a manner leaving a second binding site exposed, andwhich second binding site has binding specificity to a second materialas a label agent. This second material thereafter binds to the secondbinding site of the bi-specific antibody bound at the first site to thepain marker. The result provides a labeled marker on the pain factor viathe second material, which is tagged to the pain factor via use of thisintermediary bi-specific antibody.

It is also to be understood that the labeled marking of pain factorsherein described is of particular benefit with respect to thereafterimage the result. While imaging the “labeled pain factor” may begenerally described, it is to be understood that what is imaged by theparticular imaging modality may include without limitation: the overallconjugate or combination of label-plus-factor; the label itself; thefactor itself (e.g. to the extent modified in a recognizable way by thelabeled marking); or combinations of the above, including in furthermodes use of intermediary binding materials such as for examplebi-specific antibodies as herein described.

One particular example of a labeled marker and pain factor combinationbelieved to be useful according to certain of the embodiments hereindescribed is provided in finer detail to provide a furtherunderstanding. This relates to radiolabeled TNF-α antibodies and relatedimaging tools herein described. However, it is to be appreciated thatthis approach, though in particular highly beneficial, is exemplary ofbroader aspects of the present invention and other labeling and/ormarker modalities, or targeted vehicles such as without limitationantibodies, and/or imaging tools are contemplated and may be usedwithout departing from the intended broad scope according to variousaspects of the invention.

The invention according to further aspects provides a unique ability todirect therapy to pain, including without limitation pain associatedwith musculoskeletal joints and in particular the spine. Accordingly,the systems and methods of the invention according to furtherembodiments also include therapeutic device assemblies for deliveringsuch therapy. Such may include local drug or other chemical deliverymodalities. Or, therapeutic dosing of energy may be delivered, such asfor example radiofrequency (RF) energy delivery probes, ultrasoundprobes, high intensity focused ultrasound (HIFU), light energy (e.g.lasers for example), microwave energy, or cryovascular therapeutic toolsmay be used. By identifying where treatment is required due to theselectively visualized pain factors there, these tools may be used in amore efficient manner. Accordingly, the compositions of labeled markers,the visualization or imaging tools, and the therapeutic tools are thusused in an overall symphony that together provides beneficial healthcareresults in treating pain.

This is in particular the case with respect to back pain. For example, adisc may be identified as a source of pain, whereas lack of furtherclarity may render it difficult to treat the pain in a selective way.Often, ablation of the entire disc is not desired. According to certainfurther embodiments, the labeled marking of pain factors and relatedimaging is used to identify more specifically where pain occurs. In onemode, at least one-half of the disc is identified as the target fortherapy. In another mode, the labeled marker visualization localizes thetarget for therapy to one or more quarter quadrants of the disc. Instill further embodiments, directionally localized energy delivery, e.g.laser, ultrasound, or microwave, may be particularly beneficial forisolating the therapy to the isolated region of visualized, labeled painfactors. Furthermore, local injections of pain medication may bedirected via such targeted labeling and related imaging of painlocalization.

In another highly beneficial aspect, pain factors that are visualizedwith targeted markers as described hereunder may relate to nerves thatare located at least in part within bones. This may be the case forexample with respect to bony end-plates that are innervated withnociceptive nerve fibers. In one particular beneficial embodiment, painfactor imaging as herein described is used to locally identify one ormore particular end-plates of vertebral bodies as the pain source.Accordingly in many such instances, a basivertebral ablation tool setand method may be used to ablate the basivertebral nerve that innervatesthat end-plate. This may be done for example using a mono- or bi-polarelectrode assembly that is delivered via one or more needle or drillprobes into the vertebral body that is used to RF ablate the nervecloser to a root trunk section within the bone. Despite this particularbeneficial combination of tools and methods for treating pain in auniquely localized manner, however, it is to be appreciated that otherlocalized pain sources may be selectively visualized using a variety ofuseful targeted markers, and a variety of tools or methods may be usedto direct therapy accordingly, without departing from the presentintended scope of the present invention.

The following US Patents are herein incorporated in their entirety byreference thereto: 5,391,197 to Burdette et al.; U.S. Pat. No. 6,074,352to Hynynen et al.; U.S. Pat. No. 6,126,682 to Sharkey et al.; U.S. Pat.No. 6,231,528 to Kaufman et al.; U.S. Pat. No. 6,368,292 to Ogden etal.; U.S. Pat. No. 6,470,220 to Kraus, Jr. et al.; 6,562,033 to Shah etal.; U.S. Pat. No. 6,575,969 to Rittman III et al.; U.S. Pat. No.6,699,242 to Heggeness; U.S. Pat. No. 6,736,835 to Pellegrino et al.;U.S. Pat. No. 6,827,716 to Ryan et al.; U.S. Pat. No. 6,907,884 toPellegrino et al. The following published PCT Patent Applications areherein incorporated in their entirety by reference thereto: WO2003/059437 to Diederich et al.; and WO 03/061756 to Diederich et al.The following Published US Patent Applications are also hereinincorporate in their entirety by reference thereto: US 2004/0064137 toPellegrino et al.; and US 2004/0064136 to Papineau et al.

Various different modes of “imaging” and related tools are hereincontemplated, as apparent to one of ordinary skill to match the targetedmarker modalities employed to accomplish the general objectiveshereunder. In one regard, a variety of diagnostic tools may be used toacquire information related to the targeted pain factor(s) and relatedspacial location relative to surrounding tissues. This information maybe processed and converted into a representation that may be displayedor otherwise conveyed to a healthcare provider in a manner sufficientand useful to understand the spacial location of the associated pain.Accordingly, various different types of sensors, data acquisitionsystems, processors, and displays may be used in various combinations toconvert the labeled marking to useful information to such healthcareproviders. Many of these are commercially available in sufficient formto readily integrate with the targeted marker agents and deliverysystems herein described (which may further include therapeutic aspects)in an overall system sufficient to provide useful information in medicalpatient management.

Although the description above contains many details, these should notbe construed as limiting the scope of the invention but as merelyproviding illustrations of some of the presently preferred embodimentsof this invention. Therefore, it will be appreciated that the scope ofthe present invention fully encompasses other embodiments which maybecome obvious to those skilled in the art, and that the scope of thepresent invention is accordingly to be limited by nothing other than theappended claims, in which reference to an element in the singular is notintended to mean “one and only one” unless explicitly so stated, butrather “one or more.” All structural, chemical, and functionalequivalents to the elements of the above-described preferred embodimentthat are known to those of ordinary skill in the art are expresslyincorporated herein by reference and are intended to be encompassed bythe present claims. Moreover, it is not necessary for a device or methodto address each and every problem sought to be solved by the presentinvention, for it to be encompassed by the present claims. Furthermore,no element, component, or method step in the present disclosure isintended to be dedicated to the public regardless of whether theelement, component, or method step is explicitly recited in the claims.No claim element herein is to be construed as a “means plus function”element unless the element is expressly recited using the phrase “meansfor”. No claim element herein is to be construed as a “step plusfunction” element unless the element is expressly recited using thephrase “step for”.

1. (canceled)
 2. A method of treating back pain of a patient, the methodcomprising: delivering a substantially targeted agent that is adapted todifferentially bind to a pain factor into or adjacent a vertebralendplate of a vertebra of the patient; wherein the targeted agent isconjugated with an imaging contrast label to thereby form a targetedlabel configured to artificially label the pain factor in a mannersubstantially increasing an ability to image the pain factor with amagnetic resonance imaging (“MRI”) tool; imaging, with the MRI tool, thetargeted label coupled to the pain factor; determining whether thevertebral endplate is a pain source based on the imaging; channeling apath toward a target treatment location within bone of a vertebral bodyof the vertebra using an introducer; delivering a therapeutic devicethrough the introducer to the target treatment location within the boneof the vertebral body; wherein the therapeutic device comprises adelivery probe with an elongated body; wherein the therapeutic device isadapted to ablate nerve tissue; and using the therapeutic device,ablating a basivertebral nerve at the target treatment location withinthe bone of the vertebral body.
 3. The method of claim 2, wherein thedelivery probe comprises an ultrasound probe configured to deliverultrasound energy.
 4. The method of claim 2, wherein the delivery probecomprises a radiofrequency probe configured to deliver electricalenergy.
 5. The method of claim 4, wherein the radiofrequency probecomprises first and second electrodes in a bipolar lead assemblyarrangement.
 6. The method of claim 2, wherein the delivery probe isconfigured to deliver microwave energy.
 7. The method of claim 2,wherein the delivery probe is configured to deliver at least onetherapeutic chemical.
 8. The method of claim 2, wherein the therapeuticdevice is configured to deliver thermal energy.
 9. The method of claim2, wherein the imaging contrast label comprises an MRI contrast agent.10. The method of claim 2, wherein the pain factor comprises a nervefactor.
 11. The method of claim 2, wherein the pain factor comprises aninflammatory factor.
 12. The method of claim 2, wherein the pain factorcomprises a cellular factor.
 13. A method of treating back pain of apatient, the method comprising: delivering a substantially targetedagent that is adapted to differentially bind to a pain factor into oradjacent a vertebral endplate of a vertebra of the patient; wherein thetargeted agent is conjugated with an imaging contrast label to therebyform a targeted label configured to artificially label the pain factorin a manner substantially increasing an ability to image the pain factorwith an imaging tool; imaging, with the imaging tool, the targeted labelcoupled to the pain factor; determining whether the vertebral endplateis a pain source based on the imaging; channeling a path toward a targettreatment location within bone of a vertebral body of the vertebra usingan introducer; delivering an energy delivery assembly through theintroducer to a position at or adjacent the target treatment locationwithin the bone of the vertebral body; wherein the energy deliveryassembly is adapted to deliver a therapeutic dose of energy in asubstantially localized manner that is substantially isolated to thetarget treatment location; and wherein the therapeutic dose of energy issufficient to ablate nerve tissue; and using the energy deliveryassembly, ablating an intraosseous nerve at the target treatmentlocation within the bone of the vertebral body.
 14. The method of claim13, wherein the energy delivery assembly comprises a radiofrequencyprobe configured to deliver the therapeutic dose of energy.
 15. Themethod of claim 14, wherein the radiofrequency probe comprises first andsecond electrodes in a bipolar lead assembly arrangement.
 16. The methodof claim 13, wherein the therapeutic dose of energy is thermal energy.17. The method of claim 13, wherein the imaging tool is a magneticresonance imaging (“MRI”) tool and wherein the imaging contrast labelcomprises an MRI contrast agent.
 18. The method of claim 13, wherein thepain factor comprises an inflammatory factor.
 19. A method of treatingback pain of a patient, the method comprising: delivering asubstantially targeted agent that is adapted to differentially bind to apain factor into or adjacent a vertebral endplate of a vertebra of thepatient; wherein the targeted agent is conjugated with an imagingcontrast label to thereby form a targeted label configured toartificially label the pain factor in a manner substantially increasingan ability to image the pain factor with an imaging tool; imaging, withthe imaging tool, the targeted label coupled to the pain factor;determining a pain source based on the imaging; channeling a path towarda target treatment location within bone of a vertebral body of thevertebra using an introducer; delivering a therapeutic device throughthe introducer to the target treatment location within the bone of thevertebral body; wherein the therapeutic device is adapted to deliver atherapeutic dose of energy to the target treatment location; wherein thetarget treatment location comprises an intraosseous nerve.
 20. Themethod of claim 19: wherein the therapeutic device comprises aradiofrequency probe having first and second electrodes in a bipolarlead assembly arrangement; wherein the therapeutic dose of energycomprises electrical energy or thermal energy; wherein the imaging toolcomprises a magnetic resonance imaging (“MRI”) tool; and wherein theimaging contrast label comprises an MRI contrast agent.
 21. The methodof claim 19, wherein the pain factor comprises an inflammatory factor.